Francesco Tana, GianBattista Bolla, Anna Monzani, Maria Robuschi and Giuseppe Mancia
Guido Grassi, Anna Facchini, Fosca Quarti Trevano, Raffaella Dell'Oro, Francesca Arenare,
Independent Adrenergic Activation in Obesity
Obstructive Sleep Apnea
Print ISSN: 0194-911X. Online ISSN: 1524-4563
Copyright © 2005 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
2005;46:321-325; originally published online June 27, 2005;
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Obstructive Sleep Apnea–Dependent and –Independent
Adrenergic Activation in Obesity
Guido Grassi, Anna Facchini, Fosca Quarti Trevano, Raffaella Dell’Oro, Francesca Arenare,
Francesco Tana, GianBattista Bolla, Anna Monzani, Maria Robuschi, Giuseppe Mancia
Abstract—No agreement exists as to the mechanisms responsible for the sympathetic hyperactivity characterizing human
obesity, which has been ascribed recently to a chemoreflex stimulation brought about by obstructive sleep apnea rather
than to an increase in body weight, per se. In 86 middle-age normotensive subjects classified according to body mass
index, waist-to-hip ratio, and apnea/hypopnea index (overnight polysomnographic evaluation) as lean and obese subjects
without or with obstructive sleep apnea, we assessed via microneurography muscle sympathetic nerve traffic. The 4
groups were matched for age, gender, and blood pressure values, the 2 obese groups with and without obstructive sleep
apnea showing a similar increase in body mass index (32.4 versus 32.0 kg/m2, respectively) and waist-to-hip ratio (0.96
versus 0.95, respectively) compared with the 2 lean groups with or without obstructive sleep apnea (body mass index
24.3 versus 23.8 kg/m2and waist-to-hip ratio 0.77 versus 0.76, respectively; P?0.01). Compared with the
nonobstructive sleep apnea lean group, muscle sympathetic nerve activity showed a similar increase in the obstructive
sleep apnea lean group and in the nonobstructive sleep apnea obese group (60.4?2.3 and 59.3?2.0 versus 40.9?1.8
bs/100 hb, respectively; P?0.01), a further increase being detected in obstructive sleep apnea subjects (73.1?2.5
bursts/100 heart beats; P?0.01). Our data demonstrate that the sympathetic activation of obesity occurs independently
in obstructive sleep apnea. They also show that this condition exerts sympathostimulating effects independent of body
weight, and that the obstructive sleep apnea–dependent and –independent sympathostimulation contribute to the overall
adrenergic activation of the obese state. (Hypertension. 2005;46:321-325.)
Key Words: sleep apnea syndromes ? sympathetic nervous system ? chemoreceptors ? baroreflex
ent postganglionic muscle sympathetic nerve activity
(MSNA), and renal NE spillover rate,1–10thereby displaying
a hyperadrenergic state. This has been ascribed primarily to
the insulin-resistance state and the subsequent hyperinsulin-
emia that occurs more frequently with an increase in body
weight because in animals and human, insulin has been
shown to stimulate the sympathetic nervous system.11–15
However, it has also been ascribed to other mechanisms,
among which is the chemoreceptor stimulation brought about
by obstructive sleep apnea (OSA),16,17a condition that is also
common in obese individuals.18Indeed, OSA has been
reported to be the necessary condition for the obesity-related
sympathetic hyperactivity to occur in a study by Narkiewicz
et al19in which an increased number of sympathetic bursts to
skeletal muscle tissues was seen only when obesity and OSA
were concomitantly present.
The present study was conducted to determine the relative
contribution of the increased body weight, per se, versus OSA
ubjects with obesity are characterized by an increase in
urinary norepinephrine (NE), plasma levels of NE, effer-
in producing the sympathetic activation of human obesity.
This was obtained by directly assessing via microneurogra-
phy MSNA in lean subjects without or with OSA and
comparing the results with those obtained in age- and
gender-matched obese individuals, also without or with OSA.
The study population consisted of 86 subjects (68 males and 18
females, ranging from 35 to 52 years of age) recruited between 2001
and 2004. Recruitment criteria were based on the presence or
absence of: (1) normal body weight (body mass index ?25 kg/m2
and waist-to-hip ratio ?0.85 for females and ?0.95 for males) or
obesity (body mass index ?30 kg/m2; peripheral obesity: waist-to-
hip ratio ?0.85 for females and ?0.95 for males; visceral obesity:
waist-to-hip ratio ?0.85 for females and ?0.95 for males), and (2)
OSA newly diagnosed and determined by an apnea/hypopnea index
?5 at an overnight polysomnographic study (see below). Subjects
were excluded from the study if they had: (1) hypertension, as
defined by an office blood pressure elevation (?140 mm Hg systolic
or ?90 mm Hg diastolic or by use of antihypertensive drugs); (2)
congestive heart failure, as determined by symptoms and alterations
Received March 21, 2005; first decision April 13, 2005; revision accepted June 3, 2005.
From the Clinica Medica (G.G., A.F., F.Q.T., R.D., F.A., G.M.) and Clinica Pneumologica (F.T., A.M., M.R.), Dipartimento di Medicina Clinica,
Prevenzione e Biotecnologie Sanitarie, Universita ` Milano-Bicocca, Ospedale San Gerardo, Monza, Milan, Italy; Centro Interuniversitario di Fisiologia
Clinica e Ipertensione (G.G., G.B., G.M.), IRCCS, Milan, Italy; and Istituto Auxologico Italiano IRCCS (G.G., G.M.), Milan, Italy.
Correspondence to Prof Giuseppe Mancia, Clinica Medica, Ospedale S. Gerardo dei Tintori, Via Donizetti 106, 20052 Monza, Milan, Italy. E-mail
© 2005 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.orgDOI: 10.1161/01.HYP.0000174243.39897.6c
by guest on June 5, 2013http://hyper.ahajournals.org/ Downloaded from
in echocardiographically determined left ventricular diameters and
ejection fraction; (3) atrial fibrillation or other major cardiac arrhyth-
mias; (4) history of coronary or cerebrovascular diseases; (5) clinical
or laboratory evidence of valvular heart diseases; (6) history of
smoking or excessive alcohol consumption; (7) major concomitant
diseases, such as renal insufficiency, diabetes mellitus, and other
conditions known to affect neuroadrenergic function; and (8) chronic
drug treatment of any kind. Subjects were classified as lean subjects
without (n?27) or with (n?16) OSA and as obese subjects without
(n?18) or with (n?25) OSA. All subjects were studied on an
outpatient basis. The study protocol was approved by the ethics
committee of our institution. All subjects gave written consent to the
study after being informed of its nature and purpose.
The methodological details of the measurements made in the present
study have been reported previously.3–10,12,13,16,19Briefly, measure-
ments included body mass index, waist-to-hip ratio, sphygmomano-
metric and beat-to-beat finger (Finapres 2300; Ohmeda) systolic and
diastolic blood pressure, heart rate (electrocardiogram), respiration
rate (pneumotacograph), oxygen saturation (pulse oxymeter; Nell-
cor), and multiunit recording of efferent postganglionic MSNA
(microneurography), which provides a direct and highly reproducible
quantification of sympathetic activity.20,21They also included
plasma NE (high-performance liquid chromatography),22plasma
renin activity (radioimmunoassay),23plasma leptin (radioimmunoas-
say),24fasting plasma glucose (radioenzymatic method),25and insu-
lin (radioimmunoassay)25levels, which were determined from a
blood sample taken from an antecubital vein. From the formula
plasma insulin?fasting plasma glucose/22.5, calculation was made
of the homeostasis model assessment of insulin resistance (HOMA-
IR), which was used as an estimate of insulin resistance.25With the
exception of sphygmomanometric systolic and diastolic blood pres-
sure, as well as of the humoral and metabolic parameters, measure-
ments were displayed on thermic paper of an ink polygraph (Gould
3800). MSNA was quantified as burst frequency over time (bursts
per minute) and as burst frequency corrected for heart rate values
(bursts per 100 heartbeats). Before or after the study proper (see
below), all subjects underwent an overnight polysomnographic
recording that included an electromyogram, a thoracic and an
abdominal impedance for determining respiratory effort and thus the
obstructive nature of the apneic episodes, and an oxygen saturation
as well as a nasal and an oral airflow determination (thermistors).
The presence, absence, and severity of OSA was defined by the
number of episodes of apnea and hypopnea per hour of sleep
according to the formula: total n° of apneas?hypopneas)/total sleep
time (minutes)?60. Apnea/hypopnea index ?5 was regarded as
normal, whereas values of 5 to 15, 15 to 30, and ?30 were
considered indices of mild, moderate, and severe apnea, respectively.
Apnea was defined as a complete cessation of nasal and oral airflow
lasting ?10 s, whereas hypopnea was defined as a reduction in
airflow of ?50% of control values accompanied by an arousal or by
a decrease in oxygen saturation ?3%.26Determination of OSA
presence by a single overnight polysomnographic recording has been
shown to be highly reproducible and adequate to make diagnosis.27,28
This is confirmed by the evidence that in a group of patients followed
by the Division of Pulmonary Care of our hospital, the apnea/
hypopnea index differed by no ?5.0% when assessed in 2 different
sessions spaced from each other by a 3- to 4-week interval.
Protocol and Data Analysis
All subjects came to the laboratory in the morning. They were put in
the supine position and fitted with the intravenous cannula, micro-
electrodes for MSNA recording, and other measuring devices. Blood
samples for the assay of humoral and metabolic variables were then
taken, and blood pressure was measured 3? with a mercury
sphygmomanometer. After a 30-minute time interval, systolic blood
pressure, diastolic blood pressure, heart rate, respiration rate, oxygen
saturation, and MSNA were measured continuously during a 30-
minute basal state, with the subjects awake and in absence of any
apnea, hypopnea, or oxygen desaturation episodes. In about half of
the subjects (n?40), the microneurographic session preceded the
polysomnographic examination by 2 to 3 days, whereas in the
remaining half (n?46), it followed the polysomnographic examina-
tion by a comparable time interval. Data were collected in a quiet
room at a constant temperature of 20°C to 21°C and analyzed by a
single investigator (A.F.) unaware of the belonging of the subjects to
the 4 different groups. For all variables, baseline values from
individual subjects were averaged for each group and expressed as
mean?SEM. Comparisons between groups were made by 2-way
ANOVA. The 2-tailed t test for unpaired observations was used to
locate between-group differences. The Bonferroni correction was
used for multiple comparisons. A multivariate analysis was also
performed with age, gender, blood pressure, body mass index,
waist-to-hip ratio, leptin, HOMA index, and apnea/hypopnea index
as the independent variables and MSNA as the dependent one. A
value of P?0.05 was considered statistically significant.
As shown in the Table, the 4 groups of subjects were matched
for age and gender. Compared with OSA and non-OSA lean
individuals, body mass index and waist-to-hip ratio were
elevated similarly in obese subjects with and without OSA.
Sphygmomanometric blood pressure, finger blood pressure,
respiration rate, and plasma glucose were superimposable in
the 4 groups, whereas heart rate was greater in the obese
group with OSA than in the other 3 groups, the difference
achieving statistical significance, however, only when com-
parison was made with lean OSA individuals. Oxygen satu-
ration showed a progressive decrease from the lean to the
obese group, a further reduction being detected in obese
subjects with OSA. Compared with the 2 lean groups, plasma
insulin, HOMA index, plasma leptin, and plasma renin
activity were all increased in the obese group without OSA, a
further increase being observed in the group in which obesity
and OSA were concomitantly present.
The Figure shows the polysomnographic, plasma NE, and
MSNA data. The apnea/hypopnea index was similar in the
lean and obese groups with OSA, in either group being
markedly greater than that characterizing the corresponding
group without OSA. Compared with lean individuals without
OSA, MSNA, expressed as burst frequency over time or
corrected for heart rate, showed an increase in lean individ-
uals with OSA. The increase was similar to that of obese
individuals without OSA but less than that of obese individ-
uals with OSA, in which MSNA reached the maximal
between-group value. This was the case in male and female
subjects. In the multivariate analysis performed on the whole
studies sample, MSNA was positively related to waist-to-hip
ratio, apnea/hypopnea index, and HOMA index (?-
coefficient 0.73?0.09, 0.66?0.11, and 0.64?0.12, respec-
tively; P?0.01 for all), while showing no significant relation-
ship with the other hemodynamic and metabolic variables.
Plasma NE was greater in the 2 obese than in the 2 lean
groups, however, with no significant difference being de-
tected between OSA and non-OSA individuals.
In the present study, sympathetic nerve activity was: (1)
greater in obese subjects without OSA than in lean subjects
without OSA, (2) greater in obese subjects with OSA than in
lean subjects with OSA, and (3) greater in subjects with than
in those without OSA, regardless the presence or absence of
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obesity. This allows the following conclusions to be drawn.
(1) The sympathetic activation seen in human obesity occurs
independently on OSA; (2) OSA has a sympathostimulating
effect that is independent of body weight but additive to that
displayed by the overweight state; and (3) the OSA-
dependent and OSA-independent sympathostimulating ef-
fects contribute to the overall sympathetic hyperactivity of
Our data confirm the conclusion reached by Narkiewicz et
al19that OSA has a sympathostimulating effect and addition-
ally show that this is the case regardless of any body weight
abnormality. They are also in line with the evidence provided
by the same authors that the OSA-dependent sympathetic
stimulation plays a role in the hyperadrenergic state charac-
terizing obesity. However, they disagree with the conclusion
they draw that obesity is associated with no hyperadrenergic
state if there is no OSA because under this circumstance, our
obese individuals exhibited a clear-cut increase in MSNA
compared with the non-OSA lean controls. We can speculate
that the underestimation by Narkiewicz et al19of the non-
OSA–related sympathostimulating factors was attributable to
the high prevalence in their study of females, in whom
Anthropometric, Hemodynamic, Humoral, and Metabolic Data in Lean and Obese Subjects Without or With OSA
Body mass index (kg/m2)
Sphygmo BP (S/D, mm Hg)
Finger BP (S/D, mm Hg)
Heart rate (bpm)
Respiration rate (breaths/min)
Oxygen saturation (%)
Plasma glucose (mmol/L)
Plasma insulin (?U/mL)
HOMA index (a.u.)
Plasma leptin (mg/mL)
Plasma renin activity (mg/mL/h)
Values are mean?SEM.
Sphygmo BP indicates sphygmomanometric blood pressure (average of 3 measurements); S, systolic; D, diastolic; a.u., arbitrary units.
*P?0.01 vs lean subjects without OSA; †P?0.01 vs lean subjects with OSA; ‡P?0.05 vs lean subjects with OSA; §P?0.05 vs obese subjects
Values of apnea/hypopnea index (AHI),
plasma NE, and MSNA, expressed as
bursts per minute (bs/min) and as bursts
corrected for heart rate (bs/100 hb) in
lean subjects without (L?) or with (L?)
OSA and in obese subjects without (O?)
or with (O?) OSA. Data are shown as
means?SEM. Asterisks (*P?0.05; **
P?0.01) refer to the statistical signifi-
cance between groups.
Grassi et alSympathetic Activity and Sleep Apnea
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peripheral obesity is common at variance from visceral
obesity, which is more typical of the male gender. However,
visceral obesity is the condition that leads to a particularly
marked increase in plasma insulin, plasma leptin, and sym-
pathetic activity,8,10,15,29thus making the contribution of
factors related to obesity, per se, rather than OSA more clear.
In our study, 79% of the obese subjects were males, in
contrast with the 58% of the study by Narkiewicz et al.19
Several other results of our study deserve to be discussed.
First, as mentioned above, our data provide the first evidence
that OSA is associated with a marked MSNA increase not
only in obese but also in lean individuals. It is likely that in
both conditions, this increase originates from the stimulation
of peripheral chemoreceptors brought about by the anoxia
induced by the hypopneic–apneic episodes.17–19However, it
should be emphasized that other mechanisms are probably
involved. For example, we and others have shown that in
OSA subjects, there is an impairment of the arterial barore-
flex and thus of the ability of this mechanism to provide a
continuous restraint on sympathetic tone.30,31Furthermore, in
the lean subjects of the present study, OSA was associated
with greater values of insulin resistance (HOMA index) as
well as of leptin and plasma renin activity, similar to what
was seen in obese subjects with OSA versus those without
OSA.32–34Because insulin resistance (through hyperinsulin-
emia), leptin, and plasma renin activity (through angiotensin
II) stimulate sympathetic activity,11–15,29,35,36the possibility
exists that the OSA-dependent sympathetic activation is
attributable not only to reflex but also to metabolic factors,
the same multiple mechanisms operating in lean and obese
individuals with OSA. However, because sympathetic stim-
ulation increases insulin resistance and directly or indirectly
stimulates renin secretion from juxtaglomerular cells,36,37it is
of course also possible that the sequence of events is the
opposite. That is, the greater insulin resistance and plasma
renin activity values associated with OSA do not cause but
result from a metabolically independent sympathetic activa-
tion, possibly only originating from reflex mechanisms.
Second, for a similar body mass index value, the presence or
absence of OSA made a large difference in the degree of
sympathetic overactivity. This suggests that studies aimed at
comparing sympathetic activity in obese and lean subjects (as
well as in obese states of different severity) require the
assessment of OSA presence, which should be matched for
prevalence and severity between groups. Finally, our data
show that the assessment of sympathetic activity via plasma
NE assay is capable to detect the increase in adrenergic drive
associated with obesity but not that linked to OSA. This
confirms the limitations of the approach that measures circu-
lating levels of the adrenergic neurotransmitter as marker of
sympathetic tone shown in previous studies.2,5,10,20,21,38
The results of our study have a limitation and a clinical
implication. The limitation refers to the fact that we investi-
gated obese subjects of mild to moderate degree, and thus,
our data cannot be extrapolated safely to more severe obese
individuals in whom the relative contribution of OSA-
dependent versus OSA-independent sympathostimulating
mechanisms remain to be determined. The clinical implica-
tion is that not only obese but also lean subjects with OSA
may be exposed to the adverse effects of an increased
sympathetic drive on cardiac and vascular function.18,39They
may additionally be exposed to the adverse effect of insulin
resistance, which is the best predictor of the risk of develop-
ing diabetes mellitus.40In practical terms, this means that the
therapeutic approaches, such as continuous positive airway
pressure,41,42used in obese subjects with OSA to eliminate
the apneic episodes and to improve insulin sensitivity might
also be helpful when this condition occurs in lean individuals.
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